The circadian clock has profound impacts on living organisms on earth. It maximizes the fitness of an organism by enabling it to coordinate metabolism and behavior with its environment. However, studies that unequivocally demonstrate the fitness benefits are scarce and the underlying molecular mechanisms are poorly known. The surprising discovery that the Arabidopsis clock component, CCA1, is a key regulator of RPP4-mediated resistance against the oomycete pathogen Hyaloperonospora arabidopsidis (Hpa) leads to this first in depth study of the interplay between the circadian clock and plant immunity mechanisms. Aim 1 of this study will focus on the dissection of the regulatory circuitry between CCA1 and the resistance protein RPP4 using molecular genetics and systems approaches. A mathematical model will be made to explain how RPP4 perturbs CCA1-mediated rhythmic expression of defense genes resulting in programmed cell death of the infected cell and resistance to Hpa. Aim 2 will investigate the role of the circadian clock in systemic acquired resistance to test the hypothesis that the clock is reset during this immune response to redirect the resource to defense and promote cell survival. There are striking parallels between plant defense mechanisms and animal innate immunity. The influence of the circadian clock on animal immune responses has also been reported. However, in depth studies are challenging because of the inherent complexities of animal circadian clocks (central and peripheral) and of the microflora. Therefore, the proposed Arabidopsis-Hyaloperospora study will have a great advantage in revealing the design principles underline the interplay between the circadian clock and immunity besides providing detailed molecular mechanisms. The system perspectives on plants immune mechanisms will help us design better strategies to control crop disease and reduced the use of pesticides, which are hazardous to the environment and human health. Plant health has always had a significant impact on human health as demonstrated by the infamous Irish potato famine in 1840s, which was caused by Phytophthora infestans, a close relative of Hpa used in this study. With the world population exploding, developing better and safer agricultural practices is not a choice, but a necessity. PUBLIC HEALTH RELEVANCE: The circadian clock affects many aspects of human lives including jetlag, obesity, and immunity. However, the molecular mechanisms are poorly understood because humans have the complex central clock in the brain as well as peripheral clocks in different organs. This project will use a simpler organism, thale cress, to study how the circadian controls the timing of plant immune responses against infection and develop new ways to control crop disease and reduce the use of pesticides hazardous to human health and environment.